β-Agonist enhances type 2 T-cell survival and accumulation

BackgroundNeurohumoral modulation of immune system function is poorly understood. β-Adrenergic receptor ligands (β-agonists) subserve numerous physiologic processes but also function as pathogenic or therapeutic agents in numerous diseases with inflammatory components.ObjectivesWe sought to establish the effects of β-agonists and prostaglandin E2 (PGE2) on antigen-dependent and antigen-independent accumulation of IL-13+ (type 2) and IFN-γ+ (type 1) T cells. We also sought to clarify the mechanisms mediating the effects of these G protein–coupled receptor agonists.MethodsEffects of β-agonists or PGE2 on T-cell subtype accumulation were assessed in peripheral blood lymphocytes cultured with αCD3/CD28 or IL-2 by using flow cytometry. The role of cyclic AMP-dependent protein kinase (PKA) in mediating agonist effects was assessed by means of characterization of (1) phosphorylation of an intracellular PKA substrate and (2) T cells from patients with lupus possessing a natural defect in PKA activation.Resultsβ-Agonists, in contrast to PGE2, increased IL-2–induced accumulation of human type 2 T cells, an effect attributable to differential activation of PKA affecting regulation of cell proliferation and apoptosis. In T cells from patients with lupus exhibiting defective PKA activation, both β-agonists and PGE2 promoted an increase in type 2 T-cell accumulation.ConclusionGs-coupled receptors have the capacity to elicit prosurvival signaling in type 2 T cells, which, in most instances, is obscured by concomitant and antimitogenic PKA activation.Clinical implicationsβ-Agonists and other Gs-coupled receptor agonists have the potential to regulate T-cell development to affect disease pathogenesis or the efficacy of therapies, and variability of effect relates to the ability to stimulate PKA activity.